Multivariate Methods in Developing an Evolutionary Strategy for Tablet Formulation

The aim of this study was to develop a new strategy for choosing excipients in tablet formulation. Multivariate techniques such as principal component analysis (PCA) and experimental design were combined in a multivariate design for screening experiments. Of a total 87 investigated excipients, the initial screening experiments contained 5 lubricants, 9 binders, and 5 disintegrants, and 35 experiments were carried out. Considering a reduced factorial design was used, the resulting PCA and partial least squares (PLS) models offered good insight into the possibilities of tablet formulation. It also offered solutions to the problems and clearly gave directions for optimum formulations. Further, it offered several alternatives for achieving quality formulations. Additional experiments conducted to validate and verify the usefulness of the model were successful, resulting in several tablets of good quality. The conclusion is that a multivariate strategy in tablet formulation is efficient and can be used to reduce the number of experiments drastically. Combining multivariate characterization, physicochemical properties, experimental design, multivariate design, and PLS would lead to an evolutionary strategy for tablet formulation. Since it includes a learning strategy that continuously incorporates data for new compounds and from conducted experiments, this would be an even more powerful tool than expert systems.     

Multivariate methods in developing an evolutionary strategy for tablet formulation

The aim of this study was to develop a new strategy for choosing excipients in tablet formulation. Multivariate techniques such as principal component analysis (PCA) and experimental design were combined in a multivariate design for screening experiments. Of a total 87 investigated excipients, the initial screening experiments contained 5 lubricants, 9 binders, and 5 disintegrants, and 35 experiments were carried out. Considering a reduced factorial design was used, the resulting PCA and partial least squares (PLS) models offered good insight into the possibilities of tablet formulation. It also offered solutions to the problems and clearly gave directions for optimum formulations. Further, it offered several alternatives for achieving quality formulations. Additional experiments conducted to validate and verify the usefulness of the model were successful, resulting in several tablets of good quality. The conclusion is that a multivariate strategy in tablet formulation is efficient and can be used to reduce the number of experiments drastically. Combining multivariate characterization, physicochemical properties, experimental design, multivariate design, and PLS would lead to an evolutionary strategy for tablet formulation. Since it includes a learning strategy that continuously incorporates data for new compounds and from conducted experiments, this would be an even more powerful tool than expert systems.     

Multivariate Methods in the Development of a New Tablet Formulation: Excipient Mixtures and Principal Properties

ABSTRACT

A tablet formulation for direct compression has previously been studied using multivariate design. An optimization study of one of the most important tablet properties, disintegration time, revealed that excipients with Principal Properties (PP's) that were predicted as suitable by the model were not represented within the studied material.

The feasibility of using mixtures of excipients in the multivariate approach to tablet formulation to solve this problem has been investigated in the present study. By mixing different excipients of the same excipient class, it should be possible to obtain mixtures with the predicted PP's, which in turn should give a formulation with the desired properties. In order to investigate the utility of this approach, separate mixture designs were applied to both binders and fillers (diluents).

As reported here, the Partial Least Squares Projections to Latent Structures (PLS) model developed in the previously published screening study has been validated in the sense that the interesting region of the PP space identified in it has been shown to contain excipients, pure or mixed, that give the formulation suitable properties. Formulations with suitable properties were found with the mixture experiments. The local models also offer several alternatives for the composition of the formulation that yield the desired disintegration time.     

Non Classical Experimental Designs in Pharmaceutical Formulation

Abstract

Classical experimental designs suitable for studying the effect of the proportions of the components on the properties of a mixture are readily developed and are of optimum efficiency. Their applicability depends however on the experimental factor space having a very simple form, and because of the many limits imposed on the levels of pharmaceutical excipients in pharmaceutical dosage forms their practical use in formulation is restricted.

Methods are available for defining the experimental factor space where it is not a simplex and the number of components is too large for the space to be defined graphically. A relatively easy method of obtaining good experimental designs is to use the D-optimum criterion, where a given number of experiments is selected out of the many possible mixtures, to give a statistically optimized design.

An example of the use of this method in formulating a modified release matrix tablet, containing 5 variable components is described. One of the advantages of the method is the possibility of a step-wise approach, and this is demonstated in the present case where the formulation was carried out in two stages. The results enabled the formulation of tablets with the desired dissolution characteristics together with a fairly complete characterisation of the system.     

Multivariate Methods in the Development of a New Tablet Formulation: Optimization and Validation

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.     

Multivariate methods in the development of a new tablet formulation: optimization and validation

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.     

Multivariate methods in the development of a new tablet formulation: excipient mixtures and principal properties

A tablet formulation for direct compression has previously been studied using multivariate design. An optimization study of one of the most important tablet properties, disintegration time, revealed that excipients with Principal Properties (PP's) that were predicted as suitable by the model were not represented within the studied material. The feasibility of using mixtures of excipients in the multivariate approach to tablet formulation to solve this problem has been investigated in the present study. By mixing different excipients of the same excipient class, it should be possible to obtain mixtures with the predicted PP's, which in turn should give a formulation with the desired properties. In order to investigate the utility of this approach, separate mixture designs were applied to both binders and fillers (diluents). As reported here, the Partial Least Squares Projections to Latent Structures (PLS) model developed in the previously published screening study has been validated in the sense that the interesting region of the PP space identified in it has been shown to contain excipients, pure or mixed, that give the formulation suitable properties. Formulations with suitable properties were found with the mixture experiments. The local models also offer several alternatives for the composition of the formulation that yield the desired disintegration time.     

Nonclassical Experimental Design Applied in the Optimization of a Placebo Granulate Formulation in High-Shear Mixer

Abstract

The optimization of wet granulation in a 10-liter high-shear mixer was investigated using a nonclassical experimental mixture design. Hydroxypropylmethylcellulose, lactose, cornstarch, and microcrystalline cellulose were used as excipients of the granulate, while polyvinylpyrrolidone was used as binder. Besides the minimization of the number of experiments, the strategy applied takes into account the cost of each experiment. The introduction of such a modification allowed us to select an experimental matrix giving enough information with a relatively low number of experiments and at a minimum cost.     

Experimental Design for Pharmaceutical Process Characterisation and Optimisation Using an Exchange Algorithm

Abstract

Efficient experimental design may be used to maximise the information available from a given number of experiments (1, 2, 3, 4). In the development of new molecules the amount of drug available for formulation studies is often restricted. Thus in studying a given process the experiment is designed so that the necessary information is obtained given there is only enough material for a limited number of operations.

We have studied the effects of process variables on the characteristics of a conventional tablet formulation of a soluble drug; the factorial design was optimised by an exchange algorithm.     

Experimentally Designed Optimization of Direct Compression Tablets

Abstract

The work reported here describes the improvement of an industrial production of tablets formed by direct compression. This formulation contained 50% active substance of plant origin as a nonhygroscopic powder. The first step was to evaluate a number of direct compression excipients in preformulation tests and then make up a basic formulation providing tablets with correct characteristics. The second step was the optimization of the initial formulation using a two-level factorial experimental design. This enabled the best formulations to be selected objectively.     

Non Classical Experimental Designs in Pharmaceutical Formulation

Classical experimental designs suitable for studying the effect of the proportions of the components on the properties of a mixture are readily developed and are of optimum efficiency. Their applicability depends however on the experimental factor space having a very simple form, and because of the many limits imposed on the levels of pharmaceutical excipients in pharmaceutical dosage forms their practical use in formulation is restricted.

Methods are available for defining the experimental factor space where it is not a simplex and the number of components is too large for the space to be defined graphically. A relatively easy method of obtaining good experimental designs is to use the D-optimum criterion, where a given number of experiments is selected out of the many possible mixtures, to give a statistically optimized design.

An example of the use of this method in formulating a modified release matrix tablet, containing 5 variable components is described. One of the advantages of the method is the possibility of a step-wise approach, and this is demonstated in the present case where the formulation was carried out in two stages. The results enabled the formulation of tablets with the desired dissolution characteristics together with a fairly complete characterisation of the system.     

Tablet Formulation : Genichi Taguchi's Approach

Abstract

In this paper the Taguchi Method for studying a large number of factors and interactions with only a few experiments is shortly presented and applied to the development of a tablet formulation.     

Robustness Testing of a Tablet Formulation Using Multivariate Design

ABSTRACT

A total of 45 experiments were carried out to evaluate the robustness of two similar tablet formulations—a product of two strengths—with respect to normal batch-to-batch variation of the excipients and the active pharmaceutical ingredient. The formulations consist of 10 ingredients. Because of the differing amounts of active pharmaceutical ingredients, the two formulations also differ in the amounts of two of the diluents and one of the binders. The excipients and active pharmaceutical ingredient were characterized in terms of multiple variables, and principal properties were calculated with principal component analysis. A Plackett and Burman design was applied to the principal properties. The relationships between the design factors and two responses, mean disintegration time and mean crushing strength, were evaluated by using regression methods. Both formulations were found to be robust under controlled conditions.     

Optimization of Tablet Formulations Containing

Abstract

An optimized direct compression tablet formulation of a conventional theophylline tablet was developed using the technique of response surface methodology and successive quadratic programming (SQP). The response surfaces were obtained from fitting data generated from a secondorder uniformprecision rotatable hexagonal experimental design. The tablet formulation was optimized for mean in vitro dissolution time using disintegration time, ejection force, friability and hardness, as constraints within the experimental region by the SQP technique. The response surface model was validated by preparing and evaluating the predicted formulation. The characteristics of the tablet formulation were analyzed by principal component analysis. Sensitivity analysis for the optimal solution was performed for each constraint, while all remaining constraints were held constant. The robustness of the response surface model was evaluated by simulation for error in the compression force values.     

The Potential use of Compression Coating in the Blinding of Clinical Trial Supplies

Abstract

The use of compression coating to blind tablets for use in clinical trials has been found to be acceptable for a number of products when comparing the ‘in vitro’ dissolution rate of the manipulated and the parent tablet. The apparent dissolution rate for some products was found to be dependent upon the quantity of compression coat surrounding the parent tablet and the compaction pressure utilised. This was in some instances found to be an artifact of the paddle dissolution method resulting from coning of the compression coat excipients over the parent tablet during dissolution.     

Effect of crospovidone and hydroxypropyl cellulose on carbamazepine in high-dose tablet formulation

The aim of this study was to develop a high-dose tablet formulation of the poorly soluble carbamazepine (CBZ) with sufficient tablet hardness and immediate drug release. A further aim was to investigate the influence of various commercial CBZ raw materials on the optimized tablet formulation.

Materials and methods: Hydroxypropyl cellulose (HPC-SL) was selected as a dry binder and crospovidone (CrosPVP) as a superdisintegrant. A direct compacted tablet formulation of 70% CBZ was optimized by a 3² full factorial design with two input variables, HPC (0–10%) and CrosPVP (0–5%). Response variables included disintegration time, amount of drug released at 15 and 60?min, and tablet hardness, all analyzed according to USP 31.

Results and discussion: Increasing HPC-SL together with CrosPVP not only increased tablet hardness but also reduced disintegration time. Optimal condition was achieved in the range of 5–9% HPC and 3–5% CrosPVP, where tablet properties were at least 70 N tablet hardness, less than 1?min disintegration, and within the USP requirements for drug release. Testing the optimized formulation with four different commercial CBZ samples, their variability was still observed. Nonetheless, all formulations conformed to the USP specifications.

Conclusions: With the excipients CrosPVP and HPC-SL an immediate release tablet formulation was successfully formulated for high-dose CBZ of various commercial sources.     

Simultaneous Optimization of Capsule and Tablet Formulation Using Response Surface Methodology

Abstract

The study described herein was undertaken to simultaneously optimize the composition of tablet and capsule formulation of an insoluble experimental drug, and to learn more about the effect of the interaction between the ingredients on the basic properties of the final dosage form. Four independent variables were varied in a set of statistically designed experiments, and a number of properties evaluated. A substantial saving in development time and quantity of drug was thereby achieved.     

Optimization of Sotalol Floating and Bioadhesive Extended Release Tablet Formulations

Abstract

A novel extended release sotalol HC1 tablet formulation which possesses a unique combination of floatation and bioadhesion for prolonged residence in the stomach has been developed. Tablets were produced by direct compression. A two-factor factorial, central, composite Box-Wilson experimental design was employed to develop and optimize the tablet formulation containing 240 mg sotalol HC1. The ratio of two major bioadhesive agents, sodium carboxymethylcellulose (NaCMC) to hydroxypropylmethylcellulose (HPMC), and the ratio of two direct compressible diluents, ethylcellulose (EC) to crosspovidone, were used as formulation variables (independent variables) for optimizing tablets response parameters, such as dissolution bioadhesive capability, tablet density and required compression force for producing 6 Kg hardness tablets. The data were also analyzed by means of quadratic response surface model. Response surfaces were generated as a function of formulation variables. An optimum direct compression, bioadhesive and floating tablet formulation of sotalol HCl was achieved by considering the dissolution characteristic as primary objective and using required compression force, bioadhesive capability as constraints within the experimental region. The surface model was validated for accurate prediction of response characteristics.     

Compatibility Study Between Ketoprofen and Tablet Excipients Using Differential Scanning Calorimetry

Abstract

Differential scanning calorimetry was used to investigate the interactions between the drug ketoprofen and a number of commonly used tablet excipients. Ketoprofen was found to interact with Precirol Ato 5, magnesium stearate, Emcompress, PVP, cross-linked PVP and lactose.